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The Phenylephrine Saga—A Drug Dilemma
572
AMERICAN JOURNAL OF OPHTHALMOLOGY
ARVO is open to all professionals with an interest in the eye and vision. The pur pose of ARVO is to serve as a forum for the dissemination of scientific informa tion. This is accomplished at the annual spring meeting in Florida, and at the four regional meetings generally held in the fall. Presentations are selected by scien tific committees composed of members from the various research sections of ARVO. This year there are ten research sections: Anatomy and Pathology; Bio chemistry; Cornea; Electrophysiology; Glaucoma; Immunology and Microbiolo gy; Oculomotor Physiology; Physiology and Pharmocology; Retina; and Visual Psychophysics. Additionally, ARVO pub lishes a high quality research journal, "Investigative Ophthalmology and Visual Science," which publishes meritorious papers in the visual sciences. The organizational structure of ARVO is simple and democratic. Each of the scien tific research sections selects a member of the Board of Trustees. Each trustee serves for five years. The president and vicepresident are selected from the senior trustees. The secretary-treasurer and the editor-in-chief of "Investigative Ophthal mology and Visual Science" each are elected by the membership for a five-year term. All the members have input into both the structure and function of ARVO. Because of its devotion to honest, highquality research, the Association has risen to occupy a high position in Amer ican and international science. Its strong est efforts are always directed toward the manner in which it conducts its meetings for the benefit of ophthalmology and the visual sciences. American ophthalmology can be partic ularly proud of an organization that is unquestionably the leading scientific association in the world devoted to the scientific aspects of the visual apparatus. No one who has ever gone to the meetings
APRIL, 1978
has come away without being impressed and enlightened. The Annual Spring Meeting, aside from being in a lovely setting, provides a most exciting program of interest to every ophthalmologist. PAUL HENDKIND
T H E P H E N Y L E P H R I N E SAGA— A DRUG DILEMMA For years, ophthalmologists have used phenylephrine in 10% concentration as a primary or enhancing agent for the dilata tion of the pupil. More dilute concentra tions have been topically applied in many preparations for their vasoconstrictive properties. The company that provides the 10% concentration has clearly warned that cer tain precautions must be taken to avoid or reduce the incidence of side effects. Their product package insert, which is also published in the "Physicians' Desk Ref erence" (PDR), specifies that phenyleph rine may be contraindicated in patients with hypertension or ventricular tachy cardia, and should be used only with extreme caution in elderly patients, and patients with hyperthyroidism, bradycardia, partial heart block, myocardial disease, or severe arteriosclerosis. In obstetrics particularly, one may encounter severe persistent hypertension, or even rupture of a cerebral blood vessel during the postpartum period. The pressor response is markedly po tentiated in patients receiving a monomine oxidase inhibitor. This pressor re sponse may be potentiated by tricyclic antidepressants. Should an excessive in crease of blood pressure occur it may immediately be relieved by an alphaadrenergic blocking agent such as phentolamine. The conclusions of the paper, "Possible adverse effects from topical oc ular 10% phenylephine," published in this issue of THE JOURNAL, will confirm
VOL. 85, NO. 4 all the statements made in the PDR. The suggested guidelines are similar to those found in the PDR, and confirm other published observations such as the obser vation that topical ocular phenylephrine in the atropinized patient can enhance pressor effects and induce tachycardia in some patients. Then why publish such a paper when all the information it contains is readily available in many forms and publications? Obviously, not all ophthal mologists are familiar with these side efects. Apparently they are being frequent ly encountered, according to the National Registry of Drug-Induced Ocular Side Effects. This publication may be useful, therefore, to inform ophthalmologists about the side effects of a commonly used ophthalmic agent. Such reporting may indicate certain breakdowns in our edu cational system. Something must be wrong with a method that necessitates constant reminders of something by which each of us has already learned, but may not have kept in mind. This could be particularly true with a physician who has prescribed the drug for many years without any untoward reaction, and be lieves the agent must therefore be safe, forgetting that side effects can occur in particularly susceptible individuals. The publication of papers from the National Registry of Drug Induced Ocu lar Side Effects may be one way of reduc ing the incidence of side effects. More frequent reports of side effects of estab lished drugs might result. One hopes such reports will be read and adopted, and not skimmed over as something the reader already knows. We must keep in mind that such report ing does not give any clue to the true incidence or frequency of the side effects. It would be just as incorrect to assume that because there have been no side effects reported with weaker concentra tions of Neo-Synephrine that these side
EDITORIALS
573
effects will not be encountered with these weaker concentrations. This type of infor mation could only be properly obtained from a well-designed prospective study. This is different from side effects that have not been noted previously, such as have occurred with the use of miotics after many years, the use of practolol after a few years, and the topical and systemic use of corticosteroids after several years. The latter drugs are commonly used and highly recommended for particular con ditions. Conversely, subconjunctival and retrobulbar injection of antibiotics, the direct administration of antibiotics into the anterior chamber of the eye, and iontophoresis are recommended by many ophthalmologists although none of these has been officially approved. When does such an experimental approach move from the stage of use without Food and Drug Administration (FDA) approval to accepted standard therapy? The physi cian can be guilty of the sin of commis sion when he uses a drug with known side effects and overlooks or disregards precautions described in the package in sert or the PDR. He may be guilty of the sin of commission b y using a drug prema turely when the long-term sequelae are not known. If he fails to use a drug that may later prove to be efficacious and relatively safe, he may be guilty of the sin of omission. Would it be incorrect prac tice to withhold chloroquine therapy in a much larger dosage than has been recom mended for the treatment of rheumatoid arthritis and lupus erythematosus, or Diodoquin in the treatment of acrodermatitis enteropathica. In each instance the pa tient may have benefited tremendously from therapy. Many patients with rheu matoid arthritis or lupus erythematosus have become functioning active individu als because of chloroquine therapy. In the case of acrodermatitis enteropathica, Diodoquin kept many youngsters alive who
574
AMERICAN JOURNAL OF OPHTHALMOLOGY
otherwise would have died, nevertheless side effects occurred. Is this experimental therapy? Would it be as incorrect a prac tice to withhold such therapy as it is to have administered these drugs when they subsequently cause macular changes as with chloroquine, or optic neuropathy as with Diodoquin? Would the same apply to individuals who receive penicillamine or ethambutol and who develop optic neuropathies? How soon must a physi cian abandon such drugs as phenylephrine chloroquine, Diodoquin, or pencillamine? Should he abandon such a drug even if he believes the therapy is helpful? Can he perhaps minimize side effects as he appreciates that only a few patients will develop these undesired responses. Is there not a definite area in which the judgments, both of the courts and of our colleagues, must be tempered. The lack of boundaries in this twilight zone produces anxieties for both investi gator and therapist. Attempts to lessen the uncertainty may be unrewarding or even dangerous. A system that responds quick ly to each new report of efficacy would endorse some drugs prematurely. A body of experts could easily come to a popular but misguided conclusion. The weight of informed opinions scientifically pre sented and published, eventually influ ences practice. Definitive answers are often impossible. This paper from the FDA and the National Registry of DrugInduced Ocular Side Effects establishes simply that side effects occur. It does not indicate the true incidence or frequency. Physicians, patients, and the courts must appreciate that even when a physician is familiar with the side effects and risks of using a drug for a specific ocular purpose, he cannot always predict whether they will occur; not can he always prescribe an adequate substitute. The toxicity of phenylephrine might be reduced by diluting the concentration of the drug used. This may also reduce the
APRIL, 1978
effectiveness of the agent, and no evi dence as yet exists to prove that the weak er concentration will decrease the number of adverse reactions. This information must be accumulated. The side effects of a drug such as phenylephrine might be reduced without sacrificing efficacy by using a pro-drug such as monopivalyl phenylephrine. Such a favorable effect has been demon strated with dipivalyl epinephrine, a prodrug of epinephrine. The dipivalyl form allows the use of lower but equally effec tive concentrations. The pro-drug does not produce the same severity or frequen cy of cardiovascular effects. Side effects will probably continue to occur in patients of even the bestinformed ophthalmologists. We must do everything possibe to minimize these ef fects through better information and through the development of equally ef fective ocular drugs with fewer systemic side effects. IRVING H. L E O P O L D
Sir Stewart Duke-Elder, G.C.V.O., F.R.S., died March 27, 1978, in London after a short illness. He was 79 years old. His obituary will appear in an early issue.
CORRESPONDENCE Transvitreal Radiofrequency Diathermy Editor: In the letter to the editor, "Transvitreal radiofrequency diathermy" (Am. J. Ophthalmol. 83:282, 1977), Robert Machemer reported that after the use of a diathermy probe made by Medical Instrument Re search Associates (MIRA) for closing intravitreous new vessels, two eyes lost
AMERICAN JOURNAL OF OPHTHALMOLOGY
ARVO is open to all professionals with an interest in the eye and vision. The pur pose of ARVO is to serve as a forum for the dissemination of scientific informa tion. This is accomplished at the annual spring meeting in Florida, and at the four regional meetings generally held in the fall. Presentations are selected by scien tific committees composed of members from the various research sections of ARVO. This year there are ten research sections: Anatomy and Pathology; Bio chemistry; Cornea; Electrophysiology; Glaucoma; Immunology and Microbiolo gy; Oculomotor Physiology; Physiology and Pharmocology; Retina; and Visual Psychophysics. Additionally, ARVO pub lishes a high quality research journal, "Investigative Ophthalmology and Visual Science," which publishes meritorious papers in the visual sciences. The organizational structure of ARVO is simple and democratic. Each of the scien tific research sections selects a member of the Board of Trustees. Each trustee serves for five years. The president and vicepresident are selected from the senior trustees. The secretary-treasurer and the editor-in-chief of "Investigative Ophthal mology and Visual Science" each are elected by the membership for a five-year term. All the members have input into both the structure and function of ARVO. Because of its devotion to honest, highquality research, the Association has risen to occupy a high position in Amer ican and international science. Its strong est efforts are always directed toward the manner in which it conducts its meetings for the benefit of ophthalmology and the visual sciences. American ophthalmology can be partic ularly proud of an organization that is unquestionably the leading scientific association in the world devoted to the scientific aspects of the visual apparatus. No one who has ever gone to the meetings
APRIL, 1978
has come away without being impressed and enlightened. The Annual Spring Meeting, aside from being in a lovely setting, provides a most exciting program of interest to every ophthalmologist. PAUL HENDKIND
T H E P H E N Y L E P H R I N E SAGA— A DRUG DILEMMA For years, ophthalmologists have used phenylephrine in 10% concentration as a primary or enhancing agent for the dilata tion of the pupil. More dilute concentra tions have been topically applied in many preparations for their vasoconstrictive properties. The company that provides the 10% concentration has clearly warned that cer tain precautions must be taken to avoid or reduce the incidence of side effects. Their product package insert, which is also published in the "Physicians' Desk Ref erence" (PDR), specifies that phenyleph rine may be contraindicated in patients with hypertension or ventricular tachy cardia, and should be used only with extreme caution in elderly patients, and patients with hyperthyroidism, bradycardia, partial heart block, myocardial disease, or severe arteriosclerosis. In obstetrics particularly, one may encounter severe persistent hypertension, or even rupture of a cerebral blood vessel during the postpartum period. The pressor response is markedly po tentiated in patients receiving a monomine oxidase inhibitor. This pressor re sponse may be potentiated by tricyclic antidepressants. Should an excessive in crease of blood pressure occur it may immediately be relieved by an alphaadrenergic blocking agent such as phentolamine. The conclusions of the paper, "Possible adverse effects from topical oc ular 10% phenylephine," published in this issue of THE JOURNAL, will confirm
VOL. 85, NO. 4 all the statements made in the PDR. The suggested guidelines are similar to those found in the PDR, and confirm other published observations such as the obser vation that topical ocular phenylephrine in the atropinized patient can enhance pressor effects and induce tachycardia in some patients. Then why publish such a paper when all the information it contains is readily available in many forms and publications? Obviously, not all ophthal mologists are familiar with these side efects. Apparently they are being frequent ly encountered, according to the National Registry of Drug-Induced Ocular Side Effects. This publication may be useful, therefore, to inform ophthalmologists about the side effects of a commonly used ophthalmic agent. Such reporting may indicate certain breakdowns in our edu cational system. Something must be wrong with a method that necessitates constant reminders of something by which each of us has already learned, but may not have kept in mind. This could be particularly true with a physician who has prescribed the drug for many years without any untoward reaction, and be lieves the agent must therefore be safe, forgetting that side effects can occur in particularly susceptible individuals. The publication of papers from the National Registry of Drug Induced Ocu lar Side Effects may be one way of reduc ing the incidence of side effects. More frequent reports of side effects of estab lished drugs might result. One hopes such reports will be read and adopted, and not skimmed over as something the reader already knows. We must keep in mind that such report ing does not give any clue to the true incidence or frequency of the side effects. It would be just as incorrect to assume that because there have been no side effects reported with weaker concentra tions of Neo-Synephrine that these side
EDITORIALS
573
effects will not be encountered with these weaker concentrations. This type of infor mation could only be properly obtained from a well-designed prospective study. This is different from side effects that have not been noted previously, such as have occurred with the use of miotics after many years, the use of practolol after a few years, and the topical and systemic use of corticosteroids after several years. The latter drugs are commonly used and highly recommended for particular con ditions. Conversely, subconjunctival and retrobulbar injection of antibiotics, the direct administration of antibiotics into the anterior chamber of the eye, and iontophoresis are recommended by many ophthalmologists although none of these has been officially approved. When does such an experimental approach move from the stage of use without Food and Drug Administration (FDA) approval to accepted standard therapy? The physi cian can be guilty of the sin of commis sion when he uses a drug with known side effects and overlooks or disregards precautions described in the package in sert or the PDR. He may be guilty of the sin of commission b y using a drug prema turely when the long-term sequelae are not known. If he fails to use a drug that may later prove to be efficacious and relatively safe, he may be guilty of the sin of omission. Would it be incorrect prac tice to withhold chloroquine therapy in a much larger dosage than has been recom mended for the treatment of rheumatoid arthritis and lupus erythematosus, or Diodoquin in the treatment of acrodermatitis enteropathica. In each instance the pa tient may have benefited tremendously from therapy. Many patients with rheu matoid arthritis or lupus erythematosus have become functioning active individu als because of chloroquine therapy. In the case of acrodermatitis enteropathica, Diodoquin kept many youngsters alive who
574
AMERICAN JOURNAL OF OPHTHALMOLOGY
otherwise would have died, nevertheless side effects occurred. Is this experimental therapy? Would it be as incorrect a prac tice to withhold such therapy as it is to have administered these drugs when they subsequently cause macular changes as with chloroquine, or optic neuropathy as with Diodoquin? Would the same apply to individuals who receive penicillamine or ethambutol and who develop optic neuropathies? How soon must a physi cian abandon such drugs as phenylephrine chloroquine, Diodoquin, or pencillamine? Should he abandon such a drug even if he believes the therapy is helpful? Can he perhaps minimize side effects as he appreciates that only a few patients will develop these undesired responses. Is there not a definite area in which the judgments, both of the courts and of our colleagues, must be tempered. The lack of boundaries in this twilight zone produces anxieties for both investi gator and therapist. Attempts to lessen the uncertainty may be unrewarding or even dangerous. A system that responds quick ly to each new report of efficacy would endorse some drugs prematurely. A body of experts could easily come to a popular but misguided conclusion. The weight of informed opinions scientifically pre sented and published, eventually influ ences practice. Definitive answers are often impossible. This paper from the FDA and the National Registry of DrugInduced Ocular Side Effects establishes simply that side effects occur. It does not indicate the true incidence or frequency. Physicians, patients, and the courts must appreciate that even when a physician is familiar with the side effects and risks of using a drug for a specific ocular purpose, he cannot always predict whether they will occur; not can he always prescribe an adequate substitute. The toxicity of phenylephrine might be reduced by diluting the concentration of the drug used. This may also reduce the
APRIL, 1978
effectiveness of the agent, and no evi dence as yet exists to prove that the weak er concentration will decrease the number of adverse reactions. This information must be accumulated. The side effects of a drug such as phenylephrine might be reduced without sacrificing efficacy by using a pro-drug such as monopivalyl phenylephrine. Such a favorable effect has been demon strated with dipivalyl epinephrine, a prodrug of epinephrine. The dipivalyl form allows the use of lower but equally effec tive concentrations. The pro-drug does not produce the same severity or frequen cy of cardiovascular effects. Side effects will probably continue to occur in patients of even the bestinformed ophthalmologists. We must do everything possibe to minimize these ef fects through better information and through the development of equally ef fective ocular drugs with fewer systemic side effects. IRVING H. L E O P O L D
Sir Stewart Duke-Elder, G.C.V.O., F.R.S., died March 27, 1978, in London after a short illness. He was 79 years old. His obituary will appear in an early issue.
CORRESPONDENCE Transvitreal Radiofrequency Diathermy Editor: In the letter to the editor, "Transvitreal radiofrequency diathermy" (Am. J. Ophthalmol. 83:282, 1977), Robert Machemer reported that after the use of a diathermy probe made by Medical Instrument Re search Associates (MIRA) for closing intravitreous new vessels, two eyes lost